EP2148886B1 - Dérivés de tubulysine - Google Patents

Dérivés de tubulysine Download PDF

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EP2148886B1
EP2148886B1 EP08758446.2A EP08758446A EP2148886B1 EP 2148886 B1 EP2148886 B1 EP 2148886B1 EP 08758446 A EP08758446 A EP 08758446A EP 2148886 B1 EP2148886 B1 EP 2148886B1
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mmol
alkyl
solution
added
acoet
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EP2148886A1 (fr
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Wolfgang Richter
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R and D Biopharmaceuticals GmbH
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R and D Biopharmaceuticals GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • the present invention refers to novel cytotoxic molecules and their use for the treatment of cancer and other diseases.
  • the present invention provides a compound of Formula (IV): wherein R 2 is C 1 -C 4 alkyl, R 6 is C 1 -C 6 alkyl, R 7 is C 1 -C 6 alkyl, CH 2 OR 19 or CH 2 OCOR 20 , wherein R 19 is alkyl, especially isopropyl, R 20 is C 2 -C 6 -alkenyl, phenyl, or CH 2 -Phenyl, R 9 is C 1 -C 6 alkyl, R 10 is H, OH, O-alkyl or O-acetyl and f is 1 or 2; and wherein R 11 has the following structure: wherein R 21 is H, OH, halogen, NH 2 , alkyloxy, phenyl, alkyl amino or dialkyl amino; R 16 is H or a C 1 -C 6 -alkyl group; R 17 is CO 2 H, CO 2 R 18 , CONHNH 2 , OH, NH 2 , SH or
  • alkyl or alk refers to a saturated, linear or branched, optionally substituted hydrocarbon group, containing from one to twenty carbon atoms, preferably from one to twelve carbon atoms, mostly preferred from one to six carbon atoms, for example methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sek-butyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl.
  • alkenyl and alkinyl refers to an at least partially unsaturated, linear or branched, optionally substituted hydrocarbon group, containing from two to twenty carbon atoms, preferably from two to twelve carbon atoms, mostly preferred from two to six carbon atoms, for example ethenyl, allyl, acetylenyl, propargyl, isoprenyl, or hex-2-enyl.
  • alkenyl groups contain one or two, most preferred one double bond and alkinyl groups contain one or two, most preferred one triple bond.
  • alkyl, alkenyl and/or alkinyl refer to groups where one or several, preferentially one, two or three hydrogen atoms are replaced by a halogen atom, preferentially fluorine or chlorine or a 2,2,2-trichlorethyl, or a trifluoromethyl group.
  • heteroalkyl refers to an alkyl, alkenyl or alkinyl group, where one or more, preferentially one, two or three carbon atoms are replaced by an O, N, P, B, Se, Si, or S atom, preferentially O, S or N.
  • heteroalkyl also refers to a carboxylic acid or a group derived thereof, for example acyl (alkyl-CO), acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamid or alkoxycarbonyloxy.
  • heteroalkyl groups are groups of the formula R a -O-Y a -, R a -S-Y a -, R a -N(R b )-Y a -, R a -CO-Y a -, R a -O-CO-Y a -, R a -CO-O-Y a -, R a -CO-N(R b )-Y a -, R a -N(R b )-CO-Y a -, R a -O-CO-N(R b )-Y a -, R a -N(R b )-CO-O-Y a -, R a -N(R b )-CO-O-Y a -, R a -N(R b )-CO-O-Y a -, R a -N(R b )-CO-O-Y a -
  • heteroalkyl groups are methoxy, trifluormethoxy, ethoxy, n-propyloxy, iso-propyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, isopropylethylamino, methyl-aminomethyl, ethylaminomethyl, di-isopropylaminoethyl, enolether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl.
  • Other examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate,
  • cycloalkyl refers to a saturated or partially unsaturated (e.g. cycloalkenyl) optionally substituted cyclic group, comprising one or several rings, preferentially one or two rings, containing three to fourteen ring carbon atoms, preferentially three to ten, preferentially three, four, five, six or seven ring carbon atoms.
  • cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentenyl, spiro[4,5]-decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, cubanyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorcyclohexyl or the cyclohex-2-enyl group.
  • heterocycloalkyl refers to a cycloalkyl as defined above, wherein one or several, preferentially one, two or three ring carbon atoms are replaced by an O, N, Si, Se, P, or S, preferentially O, S or N.
  • a heterocycloalkyl group is composed of one or two rings comprising three to ten, preferentially three, four, five, six or seven ring atoms.
  • heterocycloalkyl examples include piperidyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydro-furyl, oxacyclopropyl, azacyclopropyl or 2-pyrazolinyl groups as well as lactams, lactons, cyclic imides and cyclic anhydrides.
  • alkylcycloalkyl refers to groups, which contain cycloalkyl as well as alkyl, alkenyl or alkinyl groups according to the above definition, e.g. alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkinylcycloalkyl groups.
  • an alkylcycloalkyl group is composed of a cycloalkyl group, comprising one or more rings, comprising three to ten, preferentially three, four, five, six or seven carbon - atoms and one or two alkyl, alkenyl oder alkinyl groups with one or two to six carbon atoms.
  • heteroalkylcycloalkyl refers to alkylcycloalkyl groups, according to the above definition, wherein one or several, preferentially one, two or three carbon atoms are replaced by O, N, Si, Se, P or S, preferentialy O, S or N. Preferentially it is composed of one or two ring systems with three to ten, preferentially three, four, five, six or seven ring atoms and one or two alkyl, alkenyl, alkinyl or heteroalkyl groups with one or two to six carbon atoms.
  • Examples of such a group are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkinylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocylcloalkenyl, wherein the cyclic group is saturated or partially (simply, twofold or threefold) unsaturated.
  • aryl or ar refers to an optionally substituted aromatic group, composed of one or several rings, comprising six to fourteen carbon atoms, preferentially six to ten, preferentially six carbon atoms.
  • aryl or ar can also refer to an aromatic group, wherein one or several H atoms are replaced by F, Cl, Br or I or OH, SH, NH 2 , or NO 2 . Examples are phenyl-, naphthyl-, biphenyl-, 2-fluorphenyl, anilinyl-, 3-nitrophenyl or 4-hydroxy-phenyl.
  • heteroaryl refers to an aromatic group, composed of one or several rings, comprising five to fourteen ring atoms, preferentially five to ten, whereof one or several, preferentially one, two, three or four are O, N, P or S ring atoms, preferentially O, S or N.
  • heteroaryl can also refer to groups, wherein one or several H atoms are replaced by F, Cl, Br or I or OH, SH, NH 2 , or NO 2 .
  • Examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, chinolinyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, 3-pyrazolyl and isochinolinyl.
  • aralkyl refers to groups composed of aryl and alkyl, alkenyl, alkinyl and/or cycloalkyl, e.g. arylalkyl, arylalkenyl, arylalkinyl, arylcycloalkyl, arylcycloalkenyl, alkylarylacycloalkyl and alkylarylcycloalkenyl.
  • aralkyles examples include toluol, xylol, mesitylen, styren, benzylchloride, o-fluortoluene, 1H-inden, tetralin, dihydronaphthaline, indanon, phenylcyclopentyl, cumol, cyclohexylphenyl, fluoren and indan.
  • an aralkyl group is composed of one or two aromatic rings, comprising six to ten ring carbon atoms and one or two alkyl, alkenyl and/or alkinyl comprising one or two to six carbon atoms and/or one cyclo-alkyl comprising five or six ring carbon atoms.
  • heteroaralkyl refers to an aralkyl group as defined above, wherein one or several, preferentially one, two, three or four carbon atoms are replaced by O, N, Si, Se, P, B or S, preferentially O, N or S, and to groups which contain aryl, heteroaryl and alkyl, alkenyl, alkinyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl.
  • a heteroaralkyl group is composed of one or two aromatic ring systems comprising five or six to ten carbon atoms and one or two alkyl, alkenyl and/or alkinyl comprising one or two to six carbon atoms and/or one cycloalkyl comprising five or six ring carbon atoms, wherein one, two, three or four carbon atoms can be replaced by O, N or S.
  • Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkinylheterocyclo-alkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkinyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalken-yl, heteroarylalkylcycloalkyl, heteroarylalkylhetero-cycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylhetero-cycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroary
  • Examples are tetrahydroisochinolinyl, benzoyl, 2- or 3-ethyl-indolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl.
  • cycloalkyl, heterocycloalkyl, alkylcyclo-alkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups, wherein one or several H atoms are replaced by F, Cl, Br or I or OH, SH, NH 2 , NO 2 .
  • the term "optionally substituted” relates to groups, wherein one or several H atoms can be replaced by F, Cl, Br or I or OH, SH, NH 2 , or NO 2 .
  • This term relates further to groups, which can be exclusively or additionally substituted with unsubstituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkinyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 9 heteroaryl, C 7 -C 12 aralkyl or C 2 -C 11 heteroaralkyl.
  • Compounds of Formula (IV) can comprise several chiral centers depending on their substitution pattern.
  • the present invention relates to all defined enantio and diastereo isomers as well as their mixtures in all ratios.
  • the present invention relates to all cis/trans isomers of compounds of the general Formula (IV) as well as their mixtures.
  • the present invention relates to all tautomeric forms of compounds of the general Formula (IV).
  • Examples of pharmacologically acceptable salts of compounds of Formula (IV) are physiologically acceptable mineral acids, e.g. hydrochloric acid, sulfuric acid, phorphoric acid or salts of organic acids, e.g. methansulfonic acid, p-toluenesulfonic acid, lactic acid, formic acid, trifluoracetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.
  • Compounds of Formula (IV) can be solvated, especially hydrated. The hydration can occur during the synthesis process or can be a consequence of the hygroscopic nature of the originally dehydrated compound of Formula (IV).
  • Compounds of Formula (IV), containing asymmetric carbon atoms might exist as mixtures of diastereomers, as mixtures of enantiomers or as optically pure compounds.
  • the pharmaceutical composition according to the present invention is composed of at least one compound of Formula (IV) and optionally carriers and/or adjuvants.
  • Prodrugs are also disclosed and they are composed of a compound of Formula (IV) and at least one pharmacologically acceptable protecting group, which is cleaved under physiological conditions, e.g. alkoxy, aralkyloxy, acyl or acyloxy, more precisely ethoxy, benzyloxy, acetyl or acetyloxy.
  • the present disclosure relates to conjugates comprising at least one compound of Formula (IV) and a biological molecule, e.g. oligo and poly saccharides, monoclonale antibody, lectine, PSA (prostata specific antigen) or peptidic vectors, hormones (somatostatin), vitamins (e.g. folic acid and its analogs), lipids or a synthetic polymer and if needed also a suitable linker, respectively.
  • the expression linker relates to a chemical group, which links compounds of Formula (IV) with such a biological macro-molecule. Examples of linkers are alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl linkers.
  • the use of the active agents for the preparation of drugs for the treatment of cancer is also subject of the present invention.
  • the present compounds are of interest for the prevention and/or treatment of rheumatoid arthritis, inflammatory diseases, immunological diseases (e.g. type I diabetis), autoimmune diseases, diseases of the eye, e.g. AMD (age related macular disease) or diabetic retinopathy other tumor diseases as well as for the surface treatment (impregnation) of plastic and metal implants, e.g. stents.
  • compositions according to the invention can be administered in one of the following ways: orally, including dragees, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenteral, including injectable solutions; rectal as suppositories; by inhalation, including powder formulation or as a spray, transdermal or intranasal.
  • the therapeutically used product is mixed with pharmacologically inert, anorganic or organic carriers, e.g. with lactose, sucrose, glucose, gelatine, malt, silica gel, starch, or derivatives thereof, talkum, stearinic acid or its salts, dried skim milk and the like.
  • anorganic or organic carriers e.g. with lactose, sucrose, glucose, gelatine, malt, silica gel, starch, or derivatives thereof, talkum, stearinic acid or its salts, dried skim milk and the like.
  • soft capsules one may use carriers like vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols.
  • liquid solutions and syrups For the production of liquid solutions and syrups one may use carriers for example water, alcohols, aqueous saline, aqueous dextrose, polyole, glycerin, vegatable oils, petroleum, animal or synthetic oils.
  • carriers for example water, alcohols, aqueous saline, aqueous dextrose, polyole, glycerin, vegatable oils, petroleum, animal or synthetic oils.
  • excipients like e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols.
  • aerosol formulations one may use compressed gases suitable fort his purpose like e.g. oxygen, nitrogen, noble gas and carbon dioxide.
  • the pharmaceutically useful agents may also contain additives for conservation, stabilisation, e.g. UV stabilizer, emulsifier, sweetener, aromatiser, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
  • Combinations with other therapeutic agents can include further agents, which are commonly used to treat the diseases mentioned above, especially cancer.
  • Building block (V) can be produced through peptide coupling of commercially available and known aminoacids.
  • the compounds of formulae (VI) and (VII) can be prepared in a manner, known to a person skilled in the art, c.f. for example also described in part in the Lit. ( D. Neri, G. Fossati, M. Zanda, ChemMedChem 2006, 1, 175-180 ; A. Dömling et al., Angew. Chem. Int. Ed. 2006, 45, 7235-7239 ; H.M. Peltier et al., J. Am. Chem. Soc. 128, 16018-16019, 2006 );
  • the following building blocks can be used for the preparation of compounds according to the present invention.
  • Tubulysin A has been used as reference. The results are shown in Table 1.
  • Table 1 Compound IC50 cell line [nM] HT-29 A2780 MCF-7 0.75 0.8 0.6 HT-29 A2780 NCI-H1299 3.0 0.8 1.93 HT-29 A2780 NCI-H1299 MCF-7 0.48 0.30 0.52 0.4 HT-29 0.43 HT-29 MCF-7 0.35 0.6 HT-29 MCF-7 0.28 0.4 HT-29 MCF-7 3.1 1.1 HT-29 A2780 2.1 0.7 HT-29 A2780 MCF-7 2.0 0.8 0.6 HT-29 A2780 2.3 1.4 HT-29 A2780 MCF-7 3.5 0.9 1.1 HT-29 A2780 0.49 0.3 HT-29 A2780 3.1 1.1 HT-29 MCF-7 0.45 0.4 HT-29 MCF-7 23.0 15.2 HT-29 A2780 4.3 1.6
  • the new molecules according to this invention show an activity against several cancer cell lines between 0.03 to 60 nM.

Claims (4)

  1. Composé de formule (IV),
    Figure imgb0111
     où
    R2 est un alkyle en C1 à C4 ;
    R6 est un alkyle en C1 à C6 ;
    R7 est un alkyle en C1 à C6, CH2OR19 ou CH2OCOR20, où R19 est un alkyle, R20 est un alcényle en C2 à C6, phényle ou CH2-phényle ;
    R9 est un alkyle en C1 à C6 ;
    R10 est H, OH, O-alkyle ou O-acétyle ;
    f est 1 ou 2 ;
    R11 a la structure suivante :
    Figure imgb0112
     où
    R21 est H, OH, halogène, NH2, alkyloxy, phényle, alkylamino ou dialkylamino,
    R16 est H ou un groupe alkyle en C1 à C6 ;
    R17 est CO2H CO2R18, CONHNH2, OH, NH2 SH ou un groupe alkyle, cycloalkyle, hétéroalkyle ou hétérocycloalkyle facultativement substitué, où R18 est un groupe alkyle, hétéroalkyle ou hétérocycloalkyle facultativement substitué ; et
    p est 0, 1, 2 ou 3 ;
    ou sel, solvate, hydrate pharmacologiquement acceptable ou formulation pharmacologiquement acceptable de celui-ci ;
    où l'expression « facultativement substitué » a trait à des groupes où un ou plusieurs atomes H peuvent être remplacés par F, Cl, Br ou I ou OH, SH, NH2 ou NO2 ; l'expression « facultativement substitué » a en outre trait à des groupes qui peuvent être exclusivement ou additionnellement substitués par des groupes alkyle en C1 à C6, alcényle en C2 à C6, alcynyle en C2 à C6, hétéroalkyle en C1 à C6, cycloalkyle en C3 à C10, hétérocycloalkyle à C2 à C9, aryle en C6 à C10, hétéroaryle en C1 à C9, aralkyle en C7 à C12 ou hétéroaralkyle en C2 à C11 non substitués.
  2. Composition pharmaceutique contenant un composé selon la revendication 1 et facultativement un ou plusieurs vecteurs et/ou adjuvants.
  3. Composé selon la revendication 1 ou composition pharmaceutique selon la revendication 2, à utiliser dans le traitement de tumeurs, maladies immunes, maladies auto-immunes, maladies inflammatoires et polyarthrite rhumatoïde ainsi que des modifications de surface d'implants en plastique ou en métal ou à utiliser dans le traitement de maladies cancéreuses.
  4. Utilisation d'un composé selon la revendication 1 ou d'une composition pharmaceutique selon la revendication 2, pour la préparation de conjugués comprenant au moins un composé de formule (IV) et une molécule biologique, par exemple un oligo ou polysaccharide, un anticorps monoclonal, la lectine, une PSA (antigène spécifique de la prostate) ou un vecteur peptidique, une hormone, une vitamine, un lipide ou un polymère synthétique et facultativement également un lieur ou polymère d'origine naturelle ou non naturelle, tel qu'un polymère pégylé, un amidon, une cyclodextrine ou un mélange d'un polymère synthétique avec une molécule biologique.
EP08758446.2A 2007-05-10 2008-05-09 Dérivés de tubulysine Active EP2148886B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12006311.0A EP2532673A3 (fr) 2007-05-10 2008-05-09 Dérivés de tubulysine

Applications Claiming Priority (2)

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US92878107P 2007-05-10 2007-05-10
PCT/EP2008/003762 WO2008138561A1 (fr) 2007-05-10 2008-05-09 Dérivés de tubulysine

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EP2148886B1 true EP2148886B1 (fr) 2014-02-19

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CA (1) CA2723671C (fr)
ES (1) ES2463693T3 (fr)
WO (1) WO2008138561A1 (fr)

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CA2723671A1 (fr) 2008-11-20
EP2532673A2 (fr) 2012-12-12
ES2463693T3 (es) 2014-05-29
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WO2008138561A1 (fr) 2008-11-20
US20120129779A1 (en) 2012-05-24

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